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Two different pathogenic mechanisms, dying-back axonal neuropathy and pancreatic senescence, are present in the YG8R mouse model of Friedreich ’ s ataxia

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ABSTRACT

Frataxin (FXN) deficiency causes Friedreich’s ataxia (FRDA), a multisystem disorder with neurological and non-neurological symptoms. FRDA pathophysiology combines developmental and degenerative processes of dorsal root ganglia (DRG), sensory nerves, dorsal columns and other central nervous structures. A dying-back mechanism has been proposed to explain the peripheral neuropathy and neuropathology. In addition, affected individuals have non-neuronal symptoms such as diabetes mellitus or glucose intolerance. To go further in the understanding of the pathogenic mechanisms of neuropathy and diabetes associated with the disease, we have investigated the humanized mouse YG8R model of FRDA. By biochemical and histopathological studies, we observed abnormal changes involving muscle spindles, dorsal root axons and DRG neurons, but normal findings in the posterior columns and brain, which agree with the existence of a dying-back process similar to that described in individuals with FRDA. In YG8R mice, we observed a large number of degenerated axons surrounded by a sheath exhibiting enlarged adaxonal compartments or by a thin disrupted myelin sheath. Thus, both axonal damage and defects in Schwann cells might underlie the nerve pathology. In the pancreas, we found a high proportion of senescent islets of Langerhans in YG8R mice, which decreases the β-cell number and islet mass to pathological levels, being unable to maintain normoglycemia. As a whole, these results confirm that the lack of FXN induces different pathogenic mechanisms in the nervous system and pancreas in the mouse model of FRDA: dying back of the sensory nerves, and pancreatic senescence.

No MeSH data available.


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Assessment of oxidative damage in neuronal tissues (brainstem, posterior columns, nerve roots and dorsal root ganglia). A quantitative western blot assay was developed to measure MnSOD (A), catalase (B), carbonylated proteins (C) and Bcl-2 (D). Western blots were quantified as described in Fig. 2A, but the final values were expressed as a percentage of the C57BL/6J (WT; C57) value. The carbonylated protein results (C) showed a marked increase in nerve roots, demonstrating evidence of cellular oxidative stress, but the response of antioxidant enzymes (A,B) was limited. Elevated expression of catalase in DRG (B) could prevent oxidative stress, which was reflected in the decrease in protein carbonylation (C). Increased Bcl-2 protein (D) suggested a predisposition to survival in YG8R mice. Values are expressed as mean±s.e.m.; *P≤0.05; **P≤0.01 YG8R compared with WT. Roots, nerve roots; DRG, dorsal root ganglia; PC, posterior columns.
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DMM024273F3: Assessment of oxidative damage in neuronal tissues (brainstem, posterior columns, nerve roots and dorsal root ganglia). A quantitative western blot assay was developed to measure MnSOD (A), catalase (B), carbonylated proteins (C) and Bcl-2 (D). Western blots were quantified as described in Fig. 2A, but the final values were expressed as a percentage of the C57BL/6J (WT; C57) value. The carbonylated protein results (C) showed a marked increase in nerve roots, demonstrating evidence of cellular oxidative stress, but the response of antioxidant enzymes (A,B) was limited. Elevated expression of catalase in DRG (B) could prevent oxidative stress, which was reflected in the decrease in protein carbonylation (C). Increased Bcl-2 protein (D) suggested a predisposition to survival in YG8R mice. Values are expressed as mean±s.e.m.; *P≤0.05; **P≤0.01 YG8R compared with WT. Roots, nerve roots; DRG, dorsal root ganglia; PC, posterior columns.

Mentions: To gain further insight into the biology associated with mitochondria in target tissues, we measured molecular biomarkers of oxidative stress, apoptosis and autophagy. Whereas no significant changes were observed for manganese superoxide dismutase (MnSOD; Fig. 3A), catalase was significantly increased in DRG (Fig. 3B). In addition, DRG showed a significant reduction in carbonylated proteins, as suggested by oxyblot analysis, which means that the production of oxygen-derived radicals was reduced in this tissue (Fig. 3C). In contrast, although not significant, we observed a tendency for protein oxidation in nerve roots.Fig. 3.


Two different pathogenic mechanisms, dying-back axonal neuropathy and pancreatic senescence, are present in the YG8R mouse model of Friedreich ’ s ataxia
Assessment of oxidative damage in neuronal tissues (brainstem, posterior columns, nerve roots and dorsal root ganglia). A quantitative western blot assay was developed to measure MnSOD (A), catalase (B), carbonylated proteins (C) and Bcl-2 (D). Western blots were quantified as described in Fig. 2A, but the final values were expressed as a percentage of the C57BL/6J (WT; C57) value. The carbonylated protein results (C) showed a marked increase in nerve roots, demonstrating evidence of cellular oxidative stress, but the response of antioxidant enzymes (A,B) was limited. Elevated expression of catalase in DRG (B) could prevent oxidative stress, which was reflected in the decrease in protein carbonylation (C). Increased Bcl-2 protein (D) suggested a predisposition to survival in YG8R mice. Values are expressed as mean±s.e.m.; *P≤0.05; **P≤0.01 YG8R compared with WT. Roots, nerve roots; DRG, dorsal root ganglia; PC, posterior columns.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4920149&req=5

DMM024273F3: Assessment of oxidative damage in neuronal tissues (brainstem, posterior columns, nerve roots and dorsal root ganglia). A quantitative western blot assay was developed to measure MnSOD (A), catalase (B), carbonylated proteins (C) and Bcl-2 (D). Western blots were quantified as described in Fig. 2A, but the final values were expressed as a percentage of the C57BL/6J (WT; C57) value. The carbonylated protein results (C) showed a marked increase in nerve roots, demonstrating evidence of cellular oxidative stress, but the response of antioxidant enzymes (A,B) was limited. Elevated expression of catalase in DRG (B) could prevent oxidative stress, which was reflected in the decrease in protein carbonylation (C). Increased Bcl-2 protein (D) suggested a predisposition to survival in YG8R mice. Values are expressed as mean±s.e.m.; *P≤0.05; **P≤0.01 YG8R compared with WT. Roots, nerve roots; DRG, dorsal root ganglia; PC, posterior columns.
Mentions: To gain further insight into the biology associated with mitochondria in target tissues, we measured molecular biomarkers of oxidative stress, apoptosis and autophagy. Whereas no significant changes were observed for manganese superoxide dismutase (MnSOD; Fig. 3A), catalase was significantly increased in DRG (Fig. 3B). In addition, DRG showed a significant reduction in carbonylated proteins, as suggested by oxyblot analysis, which means that the production of oxygen-derived radicals was reduced in this tissue (Fig. 3C). In contrast, although not significant, we observed a tendency for protein oxidation in nerve roots.Fig. 3.

View Article: PubMed Central - PubMed

ABSTRACT

Frataxin (FXN) deficiency causes Friedreich’s ataxia (FRDA), a multisystem disorder with neurological and non-neurological symptoms. FRDA pathophysiology combines developmental and degenerative processes of dorsal root ganglia (DRG), sensory nerves, dorsal columns and other central nervous structures. A dying-back mechanism has been proposed to explain the peripheral neuropathy and neuropathology. In addition, affected individuals have non-neuronal symptoms such as diabetes mellitus or glucose intolerance. To go further in the understanding of the pathogenic mechanisms of neuropathy and diabetes associated with the disease, we have investigated the humanized mouse YG8R model of FRDA. By biochemical and histopathological studies, we observed abnormal changes involving muscle spindles, dorsal root axons and DRG neurons, but normal findings in the posterior columns and brain, which agree with the existence of a dying-back process similar to that described in individuals with FRDA. In YG8R mice, we observed a large number of degenerated axons surrounded by a sheath exhibiting enlarged adaxonal compartments or by a thin disrupted myelin sheath. Thus, both axonal damage and defects in Schwann cells might underlie the nerve pathology. In the pancreas, we found a high proportion of senescent islets of Langerhans in YG8R mice, which decreases the β-cell number and islet mass to pathological levels, being unable to maintain normoglycemia. As a whole, these results confirm that the lack of FXN induces different pathogenic mechanisms in the nervous system and pancreas in the mouse model of FRDA: dying back of the sensory nerves, and pancreatic senescence.

No MeSH data available.


Related in: MedlinePlus